ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.10C>T (p.Gln4Ter) (rs786201042)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162425 SCV000212772 pathogenic Hereditary cancer-predisposing syndrome 2019-04-10 criteria provided, single submitter clinical testing The p.Q4* pathogenic mutation (also known as c.10C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 10. This changes the amino acid from a glutamine to a stop codon within coding exon 1. This mutation has been identified in patients with Lynch syndrome or colorectal/endometrial cancers (Baglietto L et al. J. Natl. Cancer Inst. 2010 Feb;102(3):193-201; Shirts BH et al. Genet. Med. 2016 10;18:974-81; Yurgelun MB et al. J. Clin. Oncol. 2017 Apr 1;35(10):1086-1095), and has been described as a founder mutation in the French Canadian population of Quebec (Castellsagué E et al. Clin. Genet. 2015 Jun:87(6):536-42). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000524100 SCV000253772 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-22 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant is a known common cause of Lynch syndrome in the French Canadian population of Quebec (PMID: 25318681, 20028993). This variant was found in approximately 1/400 newborns in this population, making it one of the most common Lynch syndrome variants described (PMID: 25318681). ClinVar contains an entry for this variant (Variation ID: 183723). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000199142 SCV000266087 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000202232 SCV000279088 pathogenic not provided 2021-07-07 criteria provided, single submitter clinical testing Reported as a founder variant in the French Canadian population (Castellsagu 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Baglietto 2010, Yurgelun 2015, Shirts 2016, Yurgelun 2017, Tian 2019); Observed in homozygous state in individuals with personal histories suspicious for constitutional mismatch repair deficiency (CMMR-D) syndrome (Castellsague 2014, Perez-Valencia 2020); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 32773772, 30322717, 31054147, 31604779, 30702970, 29750335, 28125075, 28135145, 28152038, 28514183, 26845104, 22949379, 25318681, 25345868, 25980754, 20028993, 31948886, 31980526, 27535533, 29485237)
Fulgent Genetics,Fulgent Genetics RCV000515243 SCV000611207 pathogenic Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2017-05-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162425 SCV000685163 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000199142 SCV000731537 pathogenic Lynch syndrome 2017-03-01 criteria provided, single submitter clinical testing The p.Gln4X variant in MSH6 has been reported in >10 individuals with MSH6-assoc iated cancers, segregated with disease in at least 4 affected relatives from 3 f amilies (Baglietto 2010, Castellsague 2015, Yurgelun 2015), is present in ClinVa r (Variation ID# 183723), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 4, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the MSH6 gene is an established disease mechanism in Lynch Syndrome. In summar y, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000202528 SCV000781779 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000202528 SCV000785255 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-06-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000199142 SCV000919725 pathogenic Lynch syndrome 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.10C>T (p.Gln4X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/270892 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported to cosegregate in 11 French-Canadian families and was determined to be a founder mutation. One individual was homozygous for the variant and consistent with CMMR-D phenotype (Castellsague_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202232 SCV001134388 pathogenic not provided 2019-04-04 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic RCV000202232 SCV000257203 likely pathogenic not provided no assertion criteria provided research
OMIM RCV000202528 SCV000257496 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-06-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353573 SCV000592561 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 p.Gln4* variant was identified in ClinVar (classified as pathogenic by Ambry Genetics, Invitae, GeneDx, and the University of Washington Department of Laboratory Medicine and as likely pathogenic by Mayo Clinic Genetic Testing Laboratories), COSMIC, COGR (classified as pathogenic by a clinical laboratory), and UMD (1x with a causal classification). This variant was identified in the genome Aggregation Database (beta, October 19th 2016) in 5 of 276350 chromosomes (freq. 0.00002). The variant was not found in dbSNP, “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database”, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium database. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Gln4* variant is predicted to lead to a premature stop codon at position 4, which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH6 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. A study by Castellsague (2015) suggests the variant is a novel founder mutation in the French Canadian population. The mutation co-segregated with cancer in 15 of 23 carriers and confers a major risk to develop EC (endometrial cancer). All available tumours from carrier individuals showed MSI and IHC loss of MSH6 protein. In addition, the mutation was found in 16 samples in a control population of 6433 newborns in Quebec (~1/400). The variant was also identified by our laboratory in 2 individuals with endometrial and uterine cancer. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Division of Human Genetics,Medical University Innsbruck RCV001254934 SCV001431025 pathogenic Turcot syndrome 2020-05-06 no assertion criteria provided research

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